Loss of NF-κB p50 function synergistically augments microglial priming in the middle-aged brain

Abstract

BackgroundWhile NF-κB p50 function is impaired in central nervous system disease, aging in non-CNS tissues, and response to reactive oxygen species, the role of NF-κB p50 in aging-associated microglial pro-inflammatory priming is poorly understood.MethodsMale NF-κB p50+/+ and NF-κB p50−/− mice at three different ages (1.5–3.0 month old, 8.0–11.0 month old, and 16.0–18.0 month old) were treated with LPS (5 mg/kg, IP) to trigger peripheral inflammation, where circulating cytokines, neuroinflammation, microglia morphology, and NF-κB p50/p65 function in brain tissue were determined 3 h later.ResultsPeripheral LPS injection in 9-month-old C57BL/6 mice resulted in lower NF-κB p50 DNA binding of nuclear extracts from the whole brain, when compared to 3-week-old C57BL/6 mice, revealing differences in LPS-induced NF-κB p50 activity in the brain across the mouse lifespan. To examine the consequences of loss NF-κB p50 function with aging, NF-κB p50+/+ and NF-κB p50−/− mice of three different age groups (1.5–3.0 month old, 8.0–11.0 month old, and 16.0–18.0 month old) were injected with LPS (5 mg/kg, IP). NF-κB p50−/− mice showed markedly elevated circulating, midbrain, and microglial TNFα when compared to NF-κB p50+/+ mice at all ages. Notably, the 16.0–18.0-month-old (middle aged) NF-κB p50−/− mice exhibited synergistically augmented LPS-induced serum and midbrain TNFα when compared to the younger (1.5–3.0 month old, young adult) NF-κB p50−/− mice. The 16.0–18.0-month-old LPS-treated NF-κB p50−/− mice also had the highest midbrain IL-1β expression, largest number of microglia with changes in morphology, and greatest elevation of pro-inflammatory factors in isolated adult microglia. Interestingly, aging NF-κB p50−/− mice exhibited decreased brain NF-κB p65 expression and activity.ConclusionsThese findings support that loss of NF-κB p50 function and aging in middle-aged mice may interact to excessively augment peripheral/microglial pro-inflammatory responses and point to a novel neuroinflammation signaling mechanism independent the NF-κB p50/p65 transcription factor in this process.

Role of RPTPβ/ζ in neuroinflammation and microglia-neuron communication

“…Taken together, the predominant extranuclear localization of NF-κB p65 and the absence of correlation between MY10 potentiation of LPS-induced microglial priming in the PFC and prototypical pro-inflammatory signaling, the data suggest the existence of an unknown promoter of microgliosis. This circumstance of potentiation of microgliosis together with the decrease of NF-κB p65 has been described in other contexts such as aging 26 and point to a novel RPTPβ/ζ mediated signaling mechanism of potentiation of LPS-induced microglial activation, which is independent of the NF-κB p65 pathway. However, a limitation of this study has to be noted.…”

Nuclear Factor κB (NF-κB)–Mediated Inflammation in Multiple Sclerosis

“…Nuclear factor κB1, however, may also have beneficial effects because NF-κB1-deficient EAE mice showed more infiltrated inflammatory cells in the CNS than control mice. Consistently, p50-deficient mice exhibit augmented microglial proinflammatory responses after peripheral injection with lipopolysaccharide (94).…”

The Pro-Inflammatory Deletion Allele of the NF-κB1 Polymorphism Is Characterized by a Depletion of Subunit p50 in Sepsis

“…Support for this concept comes from animal experiments in which p50-deficient mice developed a more severe neutrophilic inflammation with a highly elevated TNF-α expression [ 29 ]. Furthermore, a recent study also reported an amplified degree of neuroinflammation in p50 knock-out mice together with an excessively increased TNF-α expression [ 30 ]. Therefore, a lack of nuclear p50 activity, as was present in D-allele carriers in our study, appears to be the main cause of the genotype-dependent aggravated inflammatory response in septic patients.…”